Epothilones are macrocyclic lactones with useful antifungal and cytotoxic properties. Their action, as is the case with paclitaxel, is based on stabilization of microtubules, causing mitotic arrest in rapidly dividing cells and thus inhibition of the growth of tumors. For reviews, see E. Nogales, Ann. Rev. Biochem., 2000, 69:277-302; L. Wessjohann, Angew. Chem. Int. Ed. Engl. 1997, 36:715-718; Höfle et al., Angew. Chem. Int. Ed. Engl., 1996, 35:1567-1569; and K. C. Nicolaou et al., Angew. Chem. Intl. Ed. Engl., 1998, 37:2014-2045. Typical epothilones, for example epothilones A, B, C, and D, carry a methylthiazolyl side chain, as shown below. Synthetic and semi-synthetic derivatives and analogues of epothilones have been described, in which carbon atoms 12 and 13 are variously derivatized via modification of the double bond or epoxide present in epothilones A, B, C, and D. Examples are found in U.S. Pat. No. 6,399,638, issued Jun. 4, 2002, which is commonly assigned with the present application and whose entire disclosure is incorporated herein by reference.
Functionalization of the C-21 position of epothilones has been accomplished via rearrangement of thiazole N-oxides, as described by G. Höfle et al., Angew. Chem. Int. Ed., 1999, 38:1971-1974; and also in PCT international patent applications WO 98/22461 and WO 98/38192 (which are incorporated herein by reference). Alternatively, 21-hydroxy epothilones may be obtained by biotransformation (21-hydroxylation) of epothilones A-D with the aid of, for example, Sorangium cellulosum strains as described in WO 98/22461, or by Actinomycetes sp., e.g. strain SC15847 as described in WO 00/39276. The conversion of 21-hydroxy to 21-amino epothilones has been described by Höfle et al. in German patent applications DE 199 07 588 and DE 199 30 111, and in PCT international application WO 00/50423. These prior art methods utilize at least two steps, in contrast to the presently claimed invention.
The 21-amino epothilones and their derivatives are promising anti-tumor agents, however there are recognized difficulties associated with their production on a manufacturing scale. Because of the complexity of epothilone-like structures, advanced chemical intermediates must be prepared either by fermentation methods or by lengthy total syntheses, and these intermediates are accordingly expensive to produce. There remains a need, therefore, for shorter and higher-yielding processes for the preparation of 21-amino epothilones from such intermediates.